Polycystic ovarian syndrome (PCOS) affects 10 percent of reproductive-aged women and is characterized by hyperandrogenic anovulation. Hyperinsulinemia plays a key role in the mechanism of hyperandrogenic anovulation. The etiology of PCOS in the human, however, is unknown. Prenatal androgen excess in female rhesus monkeys results in ovarian, endocrinological and metabolic features in adulthood which closely resemble PCOS. In this nonhuman primate model for PCOS, we will test the hypothesis that a double insult is required to evoke hyperandrogenic anovulation. We propose that hyperandrogenism is required for hyperinsulinemia to effect hyperandrogenic anovulation (PCOS). Without hyperandrogenism, hyperinsulinemia may induce ovarian hyperandrogenism, but it will fail to induce hyperandrogenic anovulation. The Specific Aims of the proposed research are to (1) use an insulin-sensitizing agent to ameliorate hyperinsulinemia and induce ovulatory cycles in prenatally androgenized female rhesus monkeys that exhibit hyperandrogenic anovulation, (2) produce hyperinsulinemia in normo-insulinemic, hyperandrogenic, prenatally androgenized females and induce hyperandrogenic anovulation, and (3) use an anti-androgen in combination with hyperinsulinemia in normo-insulinemic hyperandrogenic, prenatally androgenized females to block insulin-induced hyperandrogenic anovulation. Eight anovulatory and 10 ovulatory prenatally androgenized females will be matched for age and body composition with 18 ovulatory controls. The 8 anovulatory androgenized females and their controls will receive 4 mg/kg of troglitazone (RezulinTm, Parke-Davis) daily for 6 months to ameliorate their hyperinsulinemia. The 10 ovulatory androgenized females and their controls will receive daily injections of insulin (Ultralente insulin, Eli Lilly) for 6 months, starting at 5U/day and incrementing to 20U/day. A 6-month Control Phase will be counterbalanced with each Treatment Phase. During all Phases, data will be collected on ovarian function and morphology, hyperandrogenism in the ovary and adrenal, changes in intra-ovarian follicular fluid content, degree of LH hypersecretion, glucose/insulin homeodynamics, and CT/DXA-determined body composition. If our hypothesis is correct, these data will establish that hyperinsulinemia results in hyperandrogenic anovulation only in prenatally androgenized female monkeys. Such results would offer novel insights into the origin and mechanism of PCOS, and would provide a unifying determinant for a multifactorial syndrome.